Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: pharmacokinetics from a dose-finding study

Abstract

Background: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E₂) doses.

Study design: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E₂, either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E₂ levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion.

Results: The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m² (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC_(0-72)) 34,181 pg*day/mL; concentration maximum (C_max) 918 pg/mL; time to maximum concentration (T_max) 3.5 h. For E_2, the C_max occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly to≤50 pg/mL for all doses by 24 h. For all subjects, the median E₂ levels remained under 35 pg/mL during treatment.

Conclusion: PK parameters of NES were not affected when paired with different doses of E₂, but E₂ levels from all three doses were lower than anticipated and no dose response was observed.

Implications: While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E₂ levels achieved were not consistent with bone protection, and a dose-response was not observed.

Keywords: Continuous cycling; Contraception; Contraceptive vaginal ring; Estradiol; Nestorone; Pharmacokinetics.

Figure 1

Subject participation in the main study (upper panel) and the PK substudy (lower panel). All PK subjects participated in the main study.

Figure 2

Median concentration of Nestorone (NES) and estradiol (E₂) observed for the main study cohort using contraceptive vaginal rings releasing 200 mcg NES with either 10, 20, or 40 mcg/day. Sampling occured twice weekly over the first 60 days of ring 1 and the last 30 days of ring 2. Breaks in lines indicates intervals of no data collection (days 61 – 83 and days 91 – 152).

Figure 3

Concentration time curves (PK substudy) for 200 mcg NES with 10,20, or 40 mcg/day E2 rings at ring initiation (ring 1), ring exchange (ring 2), and at ring removal (elimination). Upper panel, estradiol (pg/mL) and lower panel, nestorone (pg/mL). Baseline values (T = 0) for Nestorone not run (indicated by star). Hours reflect specimen time collection from initial ring placement (ring 1), ring replacement (ring 2), and following ring removal (elimination). Diamonds indicate breaks between data collection intervals.